6. PROJECT SUMMARY/ ABSTRACT Functional brain imaging techniques can identify abnormalities in brain activity patterns that may serve as an early biomarker for Alzheimer's disease (AD). Specifically, these measures have identified abnormal brain metabolism and/or reduced functional connectivity in the posterior cingulate and temporoparietal posterior association cortical regions of the brain (that are part of the "default network") in patient groups at risk for developing AD. The default network has high resting state neuronal activity potentially making it vulnerable to the formation of amyloid plaques -- one of the two hallmarks of AD pathology. People with insulin resistance (IR), including those who still maintain normal glucose tolerance (IR+ NGT), those with impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) appear to be at increased risk for Alzheimer's Disease (AD). No studies have been carried out in these fast-growing populations to identify changes in brain activity patterns that could be an early biomarker of subsequent Alzheimer's Disease. The goal of the proposed study is to evaluate such patterns in three groups of subjects with IR using functional magnetic resonance imaging (fMRI) techniques to determine whether IR subjects show abnormal brain activity patterns in the "default network" compared to control individuals with normal glucose tolerance and no IR (NGT). The brain activity pattern of the IR + NGT group is of particular interest because this group will not have been exposed to hyperglycemia and thus allowing us to better isolate the effects of IR on brain function. Because type 2 diabetes patients and those with impaired glucose tolerance also show structural changes in the medial temporal lobe and learning and memory changes that occur quite early in this disease we will evaluate our participants on tests of memory and learning and assess brain structural changes using volumetric, cortical, and shape analyses as sensitive indicators of change. We will test two primary and one secondary hypothesis using 20 subjects per group (Total N = 80). Primary Hypothesis 1: Subjects with: IR + NGT, IGT and T2DM will show reduced functional connectivity in the default network compared with participants with NGT. Primary Hypothesis 2: Subjects with IR + NGT, IGT and T2DM will show reduced deactivation of the default mode regions during a memory task compared with control participants with NGT but no IR. Secondary Hypothesis: Brain structural changes will be present in the IR+NGT, IGT and T2DM groups relative to the NGT group. This study would provide the first demonstration of an early biomarker of Alzheimer's Disease in individuals with insulin resistance. Functional, structural and cognitive assessments will help delineate characteristic changes across the phases of developing T2DM. This study has two potential long term benefits: 1) to advance research endeavors aimed at identifying the mechanism(s) by which insulin resistance may increase risk for AD and 2) to develop methods to identify at risk individuals to evaluate outcomes of early intervention for insulin resistant individuals during the prodromal phase of Alzheimer's Disease. PUBLIC HEALTH RELEVANCE: Individuals with insulin resistance appear to be at increased risk for Alzheimer's disease. In other populations, changes in brain activity patterns have been identified that may serve as early biomarkers for Alzheimer's. This study will use functional MRI to investigate whether disruptions in brain activity patterns occur in insulin resistant patients, even before the disease progresses to frank diabetes. This research will allow us to evaluate outcomes of early intervention for insulin resistant individuals during the prodromal phase of Alzheimer's disease.